The Clinical Psychopharmacology Section conducts preclinical and clinical research into the mechanisms of action of cocaine. A major component of this project, conducted in collaboration with investigators at NIDDK AND NIMH, is the synthesis and evaluation of analogs of GBR12909 as putative cocaine antagonists. The initial phase of this project has identified several promising novel agents, including the most selective dopamine uptake inhibitor reported. Another component involves investigation of the possible heterogeneity of DA transporter binding sites. This project has identified multiple binding sites for [3H]GBR12935 and [3H]BTCP, and a single binding site for [3H]mazindol. Another component of this project addresses the role of classical conditioning in cocaine-induced behavioral sensitization. These studies have demonstrated that associative learning mechanisms are involved in the acquisition of context-specific behavioral sensitization to cocaine. Another component of this project tested the leading theory of cocaine addiction, which supposes that chronic cocaine use depletes brain dopamine ' Chronic cocaine did not significantly alter the basal levels of DA or 5-HT, or the rate of L-DOPA or 5-HTP accumulation in any region. However, in chronic cocaine-treated rats, the inhibitory effect of cocaine on DA and 5-HT synthesis was greatly reduced. These data suggest that the compensatory feedback mechanisms regulating biogenic amine synthesis are desensitized by repeated cocaine injections. Clinical protocols, currently underway, 1) test the DA hypothesis of cocaine addiction by acute administration of cocaine to subjects who are on various DA receptor antagonists (ARC-170); and 2) attempt to develop a human model of context-specific behavioral sensitization to cocaine (ARC-174). The significance of these findings to drug abuse research is that increased understanding of how cocaine works will lead to the development of improved treatments.